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Researchers from the University of North Carolina and Merck are identifying promising new leads in the search for agents that may be able to purge HIV from resting CD4 cells, a key requirement for any prospect of a cure for HIV infection.

The findings, reported by David Margolis and Nancie Archin in the September 15th edition of AIDS, show that a group of compounds called class 1 HDAC inhibitors show the most promise in activating previously latent HIV within resting CD4 cells. The findings may also explain why previous studies using another HDAC inhibitor, the antiepileptic valproic acid, showed only weak effect.

After integration into the host genome HIV can remain silent within a resting CD4 cell for many years, provided that it is not stimulated into replication by signals that hit the long terminal repeat portion of the virus’s genetic code. Once stimulation occurs, a complex chain of events occurs within the cell that leads to HIV replication.

Researchers interested in curing HIV believe that the only way to do it is by purging the body of all reservoirs of latent virus, since even very small quantities of latent virus would provide enough material for an eventual resurgence of viral load to pre-treatment levels if antiretroviral therapy is removed. The only way the reservoir could be purged, according to current thinking, is by activating latent virus while giving antiretroviral treatment in order to prevent further rounds of infection.

The general consensus among researchers is that large-scale activation of latent HIV would not lead to loss of viral control, because current therapies are highly efficient at suppressing viral load, and also because the size of the reservoir of infected cells is modest in comparison to the size of the virus population prior to treatment.

However, finding ways to purge the viral reservoir will not be easy. HDAC (histone deacetylase) inhibitors have been proposed as one means; they are expected to work by inhibiting the cellular mechanism – histone deacetylation - exploited by HIV to remain silent. Previous attempts using valproic acid have not been successful, leading some to argue that the approach is flawed.

In their experiments the University of North Carolina group took a variety of HDAC inhibitors and tested their ability to summon up HIV replication from resting CD4 cells gathered from people with undetectable viral load on antiretroviral treatment.

They found that not all HDAC inhibitors stimulated viral replication to the same extent, and in particular they determined that inhibitors which target the class 1 HDAC of types 1, 2 , 3 and which also targeted the class 2 HDAC type 6 may be particularly efficient.

The findings are likely to lead to new interest in identifying HDAC inhibitors targeting these specific HDACs, and in identifying the mechanisms involved in HDAC inhibition at each of the specific sites affected by the most promising compounds.

Part of this quest will focus on identifying compounds that interfere as little as possible with other cellular processes, in order to limit toxicity. Human studies of HDAC inhibitors in HIV infection may prove next to impossible if the toxicities are substantial or poorly understood, given the relatively well-tolerated antiretroviral regimens now available.

More specific HDAC inhibitors are already in use or in development as cancer therapies, and are also being investigated for use in Alzheimer’s disease, Huntington’s disease, psoriasis and fungal infections, and work in these areas is likely to benefit HIV research.

Logged

"I have tried hard--but life is difficult, and I am a very useless person. I can hardly be said to have an independent existence. I was just a screw or a cog in the great machine I called life, and when I dropped out of it I found I was of no use anywhere else."

This is an interesting concept, however, the problem seems to be the difficulty in targeting this therapy appropriately without causing collateral damage.

"Part of this quest will focus on identifying compounds that interfere as little as possible with other cellular processes, in order to limit toxicity. Human studies of HDAC inhibitors in HIV infection may prove next to impossible if the toxicities are substantial or poorly understood, given the relatively well-tolerated antiretroviral regimens now available"

Even though veritas makes a good point, there seem to be ways to get around HDAC inhibitor's possible potential toxicity, which is what the researchers who developed the "shock and kill" approach were able to do, albeit in vitro; note that they used class 1, which the North Carolina researchers found to be "particularly efficient:"

To overcome this [toxicity] problem, the Italian researchers tested a collection of HDAC inhibitors, some of which specifically target only certain enzyme isoforms (class I HDACs) that are involved in HIV latency. The toxicity of this approach, however, was not markedly decreased, although it compromises a more limited number of cellular pathways. Moreover, at non-toxic quantities, class I HDAC inhibitors were able to induce the 'awakening' of a portion of cells within a latently infected cell population. The researchers then repeated the experiment adding a drug inducing oxidative stress, buthionine sulfoximine (BSO). The results showed that BSO recruited cells non-responsive to the HDAC inhibitors into the responding cell population. An important result was that the infected cells' 'awakening' was followed by cell death, whereas the non-infected cells were left intact by the drug combination.

HDAC inhibitor's potential toxicity appears to be a crossable hurdle. The fact that they're already "in use or in development as cancer therapies, and are also being investigated for use in Alzheimer’s disease, Huntington’s disease, psoriasis and fungal infections," is very promising indeed.